oral disintegrating tablets 2015

7/26/2019 Oral Disintegrating Tablets 2015

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ORAL DISINTEGRATING TABLETS

Agus Siswanto


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Oral Disintegrating Tablets

A solid dosage form containing medicinalsubstance or active ingredient whichdisintegrates rapidly usually within a matter of

seconds when placed upon the tongue (FDA) Uncoated tablets intended to be placed in the

mouth where they disperse rapidly beforebeing swallowed and as tablets which should

disintegrate within 3 min (EuropeanPharmacopoeia )


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Drug selection criteria

Ability to permeate the oral mucosa

At least partially non-ionized at the oral cavity pH

Have the ability to diffuse and partition into the

epithelium of the upper GIT Small to moderate molecular weight

Low dose drugs preferably less than 50 mg

Short half life and frequent dosing drugs are unsuitable

for ODT Drug should have good stability in saliva and water

Very bitter or unacceptable taste and odor drugs areunsuitable for ODT


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Choice of drug candidate

No bitter taste

Good stability in water and saliva

Dose should be low as possible

Unsuitable drug candidate for orally disintegratingtablet should include:

Short half-life and frequent dosing Drug having very bitter taste

Required controlled or sustained release


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Advantages of ODT

Improved patient compliance Rapid onset of action and may offer an improved

bioavailability

Useful for pediatric, geriatric and psychiatric patients

Suitable during traveling where water is may not beavailable

No specific packaging required, can be packaged inpush through blisters

Smooth mouth feel and pleasant taste

Conventional manufacturing equipment

Cost effective

Good chemical stability as conventional oral soliddosage form


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Characteristics of an Ideal ODT

Utilizes cost effective production method

Require no water for oral administration

Dissolve / disperse/ disintegrate in mouth in a

matter of seconds Have a pleasing mouth feel and taste masking.

Less friable and have sufficient hardness

Leave minimal or no residue in mouth after

administration Manufacturing using conventional manufacturing

method


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Basic approaches to develop Oral Disintegrating Tablets

porous structure

highly water-soluble

excipients

appropriate disintegrating

agents


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Techniques in preparation of ODT

1. Freeze drying or

Lyophilization

2. Spray Drying

3. Direct Compression

4. Sublimation

5. Cotton Candy Process6. Mass Extrusion

7. Moulding

8. Nanonization

9. Fast Dissolving Films10. Phase transition

process

11. Melt granulation


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Freeze drying or Lyophilization

Lyophilization means drying at low temperature undercondition that involves the removal of water bysublimation

Drug in a water soluble matrix which is then freeze

dried to give highly porous structure The tablets prepared by lyophilization disintegrate

rapidly in less than 5 seconds due to quick penetrationof saliva in pores when placed in the oral cavity

Lyophilization is useful for heat sensitive drugs i.e.thermo-labile substances

Ex. Loratidine (Claritin Reditab and Dimetapp QuickDissolve)


10/45Freeze drying or Lyophilization


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Spray drying

Spray drying can produce highly porous and finepowders that dissolve rapidly

This technique is based on a particulate support

matrix, which is prepared by spray drying anaqueous composition containing support matrixand other components to form a highly porousand fine powder

This then mixed with active Ingredients andcompressed into tablets

Ex. Hyoscyamine Sulfate ODT


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Spray drying


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Direct compression

This is most popular technique because of its easyimplementation and cost-effectiveness Direct compression represents the simplest and most cost

effective tablet manufacturing technique

This technique can now be applied to preparation ofODT because of the availability of improved excipientsespecially superdisintegrants and sugar basedexcipients

The basic principle involves addition of disintegrantsand/or water soluble excipients and/or effervescentagents

Superdisintegrants in optimum concentration (about 2-5%) are mostly used so as to achieve rapid

disintegration along with the good mouth feel


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(a) Superdisintegrants

In many orally disintegrating tablettechnologies based on direct compression, theaddition of superdisintegrants principally

affects the rate of disintegration and hencethe dissolution

The presence of other formulation ingredientssuch as water-soluble excipients andeffervescent agents further hastens theprocess of disintegration


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Mechanism of Superdisintegrants

Swelling

Porosity and capillary action (Wicking)

Due to disintegrating particle/particlerepulsive forces

Due to deformation


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1. Swelling

Perhaps the most widely accepted general mechanismof action for tablet disintegration is swelling

Tablets with high porosity show poor disintegrationdue to lack of adequate swelling force

On the other hand, sufficient swelling force is exertedin the tablet with low porosity

It is worthwhile to note that if the packing fraction isvery high, fluid is unable to penetrate in the tablet anddisintegration is again slows down


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2. Porosity and capillary action

(Wicking)

Disintegration by capillary action is always the firststep.

When we put the tablet into suitable aqueous medium,the medium penetrates into the tablet and replaces

the air adsorbed on the particles, which weakens theintermolecular bond and breaks the tablet into fineparticles.

Water uptake by tablet depends upon hydrophilicity ofthe drug /excipient and on tableting conditions.

For these types of disintegrants maintenance of porousstructure and low interfacial tension towards aqueousfluid is necessary which helps in disintegration bycreating a hydrophilic network around the drug

particles


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3 D t di i t ti


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3. Due to disintegrating

particle/particle repulsive forces

Another mechanism of disintegratn attempts to explainthe swelling of tablet made with nonswellabledisintegrants.

Guyot-Hermann has proposed a particle repulsiontheory based on the observation that nonswellingparticle also cause disintegration of tablets.

The electric repulsive forces between particles are themechanism of disintegration and water is required for

it.

Researchers found that repulsion is secondary towicking.


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4. Due to deformation

During tablet compression, disintegranted particles getdeformed and these deformed particles get into theirnormal structure when they come in contact withaqueous media or water.

Occasionally, the swelling capacity of starch wasimproved when granules were extensively deformedduring compression.

This increase in size of the deformed particles produces

a break up of the tablet.

This may be a mechanism of starch and has onlyrecently begun to be studied.


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(b) Sugar Based Excipients

This is another approach to manufacture ODTby direct compression

The use of sugar based excipients especially

bulking agents like dextrose, fructose, isomalt,lactilol, maltilol, maltose, mannitol, sorbitol,starch hydrolysate, polydextrose and xylitol,which display high aqueous solubility andsweetness, and hence impart taste maskingproperty and a pleasing mouthfeel


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Mizumito et al have classified sugar-based

excipients into two types on the basis ofmolding and dissolution rate

Type 1 saccharides

exhibit low mouldability but high dissolution rate

lactose and mannitol

Type 2 saccharides

exhibit high mouldability and low dissolution rate

maltose and maltilol


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MANUFACTURING STEPS FOR DIRECT COMPRESSION


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Sublimation

This technique is based on the use of volatileingredients (e.g. camphor, ammoniumbicarbonate, naphthalene, urea, urethane

etc.) to other tablet excipients and themixture is then compressed into tablets

Entrapped volatile material is then removedvia sublimation, which leads to formation of aporous structure

Ex. Phloroglucinol Hydrate (Spasfon Lyoc)

S I l d i bli i


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Steps Involved in sublimation


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Cotton candy process

Involves the formation of matrix of

polysaccharides by simultaneous action of

flash melting and spinning

This candy floss matrix is then milled andblended with active ingredients and

excipients after re-crystallization and

subsequently compressed to FDT

Characteristics: It can accommodate high doses

of drug and offers improved mechanical strength

Ex- Tramadol HCl (Relivia Flash dose)


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Mass-Extrusion

Involves softening the active blend using thesolvent mixture of water soluble polyethyleneglycol, methanol and expulsion of softenedmass through the extruder or syringe to get acylindrical shape of the product into evensegments using heated blade to form tablets

Characteristics: The dried product can be used

to coat granules of bitter tasting drugs andthereby masking their bitter taste

Ex. Zolmitriptan (Zolmig ZMT)


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Moulding

water-soluble ingredients with a hydro-alcoholic solvent is used and is moldedinto tablets under pressure lower than that

used in conventional tablet compression Characteristics: Molded tablets are very

less compact than compressed tabletporous structure that enhances

disintegration/ dissolution and finallyabsorption increased


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Nanonization

Involves size reduction of drug to nanosize bymilling the drug using a proprietary wet-millingtechnique

The Nanocrystals of the drug are stabilized againstagglomeration by surface adsorption on selectedstabilizers, which are then incorporated into FDTs

Characteristics: It is used for poorly water soluble drugs

It leads to higher bioavailability and reduction in dose,cost effective manufacturing process, conventionalpackaging due to exceptional durability and wide rangeof doses (up to 200 mg of drug per unit)


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Ing. and Tech. Used for Formulating FDT:

Drug Disint.Agent

s

Other form. Ing. Tech. used Disint. Time

NSAIDS Crospovidon

e

(intragranula

&

Extragranula

r)

Mcc,Aerosil,

Mag.

stearate, stearic

acid

Wet granulation &

Direct

Compression

50 sec

(for 125

mgTab.)

Sildenafil

granulesCross linked

povidone

Lemon flavor,

aspartame,

mannitol

Freeze drying< 30 sec

Ascorbic

acid

Avicel ph

101

Pregelatinized

starch,

Moulding, Direct

Compression31-37 sec


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Preformulation studies of ODT

Powder flow properties

Bulk Density (Db)

Tapped Density (Dt) Angle of Repose

Carrs index (or) % compressibility

Hausner ratio


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Evaluation test for ODT

General Appearance Hardness

Drug Content

In-Vitro drug release

Modified disintegrationtest

Moisture uptake study

Weight variation Friability (F)

Wetting time & Water

absorption Ratio

Powder X-ray diffraction In-vitro dispersion time

Stability study


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Wetting time and water absorption ratio

Wetting time of dosage form is related to

with the contact angle.

Wetting time of the ODT is another

important parameter, which needs to be

assessed to give an insight into the

disintegration properties of the tablet.

Lower wetting time implies a quickerdisintegration of the tablet.


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The wetting time of the tablets can be measured by

using the simple procedure.[29] Five circular tissue

papers of 10cm diameter are placed in a petridish. Ten

milliliters of water soluble dye solution is added to

petridish. A tablet is carefully placed on the surface ofthe tissue paper. The time required for water to reach

upper surface of the tablet is noted as the wetting time.


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water absorption ratio

The weight of the tablet before keeping in

the petridish is noted (Wb)

The wetted tablet from the petridish is

taken and reweighed (Wa)

The water absorption ratio, R can be the

determined according to the following

equation

R = 100 (Wa-Wb) / Wb


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Disintegration test

The time for disintegration of ODTs is generally


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Modif ied disintegration test

The standard procedure of performing disintegration test for

these dosage forms has several limitations and they do not

suffice the measurement of very short disintegration times.

The disintegration time for ODT needs to be modified as

disintegration is required without water, thus the test shouldmimic disintegration in salivary contents.

For this purpose, a petridish (10 cm diameter) was filled with

10 ml of water.

The tablet was carefully put in the center of petridish and thetime for the tablet to completely disintegrate into fine particles

was noted.


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Dissolution test

Commonly the drugs may have dissolution conditions asin USP monograph

Other media such as 0.1 N HCl, pH 4.5 and pH 6.8

buffers should be used for evaluation of ODT in the

same way as their ordinary tablet counterparts Experience has indicated that USP 2 paddle apparatus

is most suitable and common choice for dissolution test

of ODT tablets, where a paddle speed of 50 rpm is

commonly used

Typically the dissolution of ODTs is very fast when using

USP monograph conditions

Hence slower paddle speeds may be utilized to obtain a

comparative profile.


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Patient counseling points for ODT

Patients may mistake ODT for effervescent tablets,

pharmacist need to be clearly told about the different

between them

ODT need to be handled carefully because some of ODT

developed may not have sufficient mechanical strength

Patients with dryness of mouth or with siogrens

syndrome or who taking anticholengic drugs may not be

suitable population for administering ODT.

Although no water is needed to allow the drug to dispensequickly and efficiently but most technologies of ODT utilizes the

body own salivation but decreased volume of saliva may slow

down dissolution/ disintegration/ bioavailability of the product


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Although chewable tablets have been in the market for

long time, patients need to be counseled properly the

difference between chewable and ODT tablets

ODT can be used easily in children who have lost their primary

teeth but do not have full use of their permanent teeth and alsofor geriatric patients who have lost their teeth permanently.


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TERIMAKASIH

oral disintegrating tablets 2015

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